Derivatives of oxopiperazinoalkylhalophenothiazines



DERIVATIVES QEQXOPIPERAZINOALKYLHAEO- PHENOTHIAZINESL Jolnr..W; Cusic,.Sirokie, Harman S.. Lowrie, Northbrook, and Henry William, Sause, Deerfield, ll l., assignors to {I}. D. Searle & Co., Chicago, III., a corporation of linois No Drawing- Application September 20, 1955, Serial No, 535,522

7 Claims. ((11,.2160-243)? The.-present invention relates toa new group of x0 piperazine derivatives and, more particularly, to derivaa tlVfiS-g of oxopiper-azinoalkylhalophenothiazinesv which can be represented by the general structuraLformulalower sir- 11 and the non-toxic salts thereof, wherein nis .0, l, or 2, X is fluorine or chlorine, Alk is aloweralkylene radical and R is a member of the class consisting of hydrogen, lower alkyl and lower aralkyl radicals;

In the foregoing structural formula Alk represents a bivalent, saturated aliphatic hydrocarbon radical derived from a straight or branched chain hydrocarbon such as ethylene, propylene, butylene, amylene, hexylene or a polymethylene radical such as trir'nethylene, tetramethylene, pentarnethylene and hexamethylene. The radical R can represent a lower alkyl radical such as methyl, ethyl, straight and branched propyl, butyl, amyl and hexyl radicals. It can also represent an aralkyl radical such as bengyl, phenethyl, tolylmethyl and the like.

The organic bases of the; foregoing type; form. pharmaceutically acceptable non-toxic salts. with.a. variety of inorganic and strong organic acids including. sulfuric, phosphoric, hydrochloric, hydrobromic, sulfarn ic, citric, ascorbic, and related acids. They'also form, quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. Among such; esters are. methyl chloride and bromide, ethyl chloride, propyl chloride, butyl chloride, isobutyl. chloride, benzyl chloride and bromide, phenethyl brornide -naphthyl chloride, dimethyl sulfate, diethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The oxopiperazine derivatives of. this invention; have valuable pharmacological properties particularly in the production of ataraxiain states of hyperirritabjility. They alsoare anti-emetic agents. Aspecial advantageof these compounds: over other halophenothiazine. derivatives: is their relative freedom fromtoxic side reactions.

The, compounds of this .invention are conveniently prepared by the condensationof a compound ofthe struc-v tural. formula I; Alk-Halogen 2,787,617 Patented. Apr, 2,, 195.7.

with an oxopiperazine of the type HN \N-R (lower alkyl)? An alternative method for preparing these compounds consists in the treatment ofa halophenothiazine with a compound; of the type Halogen-Alkr-N- (lower elkyl) j 0 The 4'-substituted derivatives can also be prepared by Example 1 A mixture of'89.3 p arts ofZ-chl'oro-lO-(fi-chloroethyl phenothiazine, 30 parts of'Z-piperazinone and 45.4 parts of sodium iodide in 1600 parts'of butanone is stirred and refluxed for-24 hours. The mixture is cooled, filtered, and evaporated to dryness and the resulting oil is dissolved in a mixture of ether and benzene, washed first with 5% sodium carbonate and then with water. The resulting organic layer is extracted with dilute hydro-- chloric acid. The extract is made alkaline with dilute sodium hydroxide and extractedwith benzene. This extract is' washed with water, dried over anhydrous potassium carbonate, filtered and evaporated. The residue is distilled'in a short-path distillation tube at 0.5-2 mm. pressure and about 260-270" C; to yield 2-chloro-10- 13- 3 -oxopiperazinyl ethyl] phenothiazine.

Use-of 211' parts of 3-chloro-10,-(fi-chloroethynphenothiazine instead of the 2-chloro isomer used hereinabove yields 3-cnloro 10 [fl-(3'-oxopiperazinyl)ethylJphenothiazine; which is distilled at about 0.1 mm. pressure and a jacket temperature of about 250 C.

Example 2 A mixture of 6 8parts of Z-pipera'zinone, 211 parts of 2- chloro '10 ('y-chloropropyl)phenothiazine, 48 parts of potassium carbonate. and 102 parts of sodium iodide is ,preparedin 4000 parts of butanone, stirred for 16 hours, andthen refiuxedand stirred'for 8 hours. The mixture iscooled, filtered, and evaporated to dryness. The resulting oil is dissolved in benzene, washed with water and then extracted with dilute hydrochloric acid. The extract is made alkaline with dilute sodiumhydroxide and extracted with benzene. This extract is washed with water, dried over anhydrous potassium carbonate, filtered and evaporated; Vacuum distillation at 0.1 mm. pres.- sure ina shortrpath distillation tube by heating the jacket to about 250? C. yields '2 chloro lQ-[y-(Y-oxopipera n l)rprony lpheno hiazinen, r y tallization from '25'prop'anoljwhite. crystals are obtained which melt at about;132'-1;35 C i A bl ti no hi as in. a mixture, of ethanol and benzene is treated with an excess of anhydrous hydrogen chloride in Z-propanol: The cooled mono-hydrochloride A/\ k i -c1 CHz-CO (CH2) s-1:3\ /NH 1 CHz-CH not Example 3 A mixture of 43.1 parts of 2 chloro IO-(fl-chloropropyl)phenothiazine, 14 parts of Z-piperazinone, 20.9 parts of sodium iodide and 440 parts of butanone is re flnxed for 40 hours and then concentrated to a small volume. The residue is taken up in Water and ether. The ether layer is separated, washed with water and extracted with 2-N hydrochloric acid. This extract is made alkaline by addition of 6-N sodium hydroxide and extracted with. ether. The ether solution is washed to nontrality, dried over potassium carbonate, and evaporated to yield 2 chloro 10-[5-(3-oxopiperazinyl)-propyl]- phenothiazine melting at about 9096 C.

Example 4 13 parts of N-phenyl 4 fiuoroanthranilic acid are heated to about 270 C. for 90 minutes and then dissolved in ether. The ether solution is washed with 2-N 1 sodium hydroxide and with water and then dried over anhydrous sodium sulfate. After evaporation of the other the residue is distilled at about 0.05 mm. pressure and 70 C. to yield rn-fluorodiphenylamine as a colorless oil. A mixture of 3.7 parts of this oil, 1.3 parts of sulfur and 0.1 part of iodine are heated at l80185 for an hour. The residue is sublimed in vacum and then crystallized repeatedly from ethanol to yield 2-fiuorophenothiazine melting at about 20020l C.

A solution of 217 parts of 2-fiuorophenothiazine in 550 parts of other is treated under a nitrogen atmosphere by gradual addition with 64 parts of butyl lithium in 500 parts of ether. The mixture is stirred and then treated with 263 parts of 6-chlorobutyl p-toluenesulfonate and 200 parts of ether. is added a solution of 180 parts of concentrated hydrochloric acid in 300 parts of water, after which the hydrolyzed mixture is filtered. The organic layer is separated from the filtrate, washed with water and concentrated to yield 2-fiuoro l (ti-chlorobutyl)phenothiazinc.

A mixture of 6.2 parts of this compound, 3 parts of sodium iodide, 10 parts of Z-piperazinone and 400 parts of butanone is refluxed for 8 hours and then concentrated. The residue is extracted with dilute hydrochloric acid. This extract is rendered alkaline by addition of dilute sodium hydroxide solution and then extracted with benzene. The benzene extract is washed with water, dried over anhydrous calcium sulfate, filtered and evaporated to yield 2 fluoro l0 [6-(3'-oxopiperazinyl)- butyl1phenothiazine which is vacuum distilled in a shortpatn distillation tube at 0.5-2 mm. pressure by heating the jacket to about 250 C.

Example A mixture of 6.2 parts of 2-chl0ro v 10 ('y-chloropropyl)phenothiazine, 2.3 parts of 3-methy1 2 piperazinone, 1.4 parts of potassium carbonate and 3 parts of sodium iodide in 400 parts of butanone are stirred at room temperature for hours and then refluxed for 7 hours with stirring. After cooling, the reaction mixture is filtered and the filtrate is concentrated under vacuum to an oily residue. The latter is dissolved in a mixture of ether and benzene and washed successively with dilute sodium hydroxide and water and then extracted with After an hour of stirring, there l dilute hydrochloric acid. This extract is washed with ether, rendered alkaline with dilute sodium hydroxide and extracted with a mixture of ether and benzene. This extract is washed thoroughly with water, dried and evapo rated. Vacuum distillation of the residue at 0.2 mm. pressure in a short-path distillation tube by heating the jacket to about 265 C. yields 2-chloro-l0-[ -(2'-methyl- 3-oxopiperazinyl)propyl]phenothiazine. Treatment of an ethanolbenzene solution of this base with an excess of anhydrous hydrogen chloride in Z-propanol yields a mono-hydrochloride which, in crude form, melts at about l28-136 C.

Example 6 A mixture of 6.2 parts of 2-chloro 10 (y-chloropropyl)phenothiazine, 2.6 parts of 3,3-dimethyl-2-piperazinone, 3 parts of sodium iodide and 1.4 parts of potassium carbonate in 160 parts of Z-butanone is permitted to stand at room temperature for 15 hours and then refluxed with stirring for 6 hours. The mixture is chilled, filtered and evaporated to dryness and the resulting oil is dissolved in benzene. This solution is washed with water and then extracted with dilute hydrochloric acid. This extract is made alkaline by addition of dilute potassium hydroxide and extracted with benzene. The benzene solution is washed with water, dried over anhydrous calcium sulfate, filtered and evaporated. Vacuum distillation at 0.2 mm. pressure and a jacket temperature of about 265 C. in a short-path distillation tube yields 2 chloro 10 ['y-(2'-dimethyl-3-oxopiperazinyl)propyllphenothiazine. Treatment of ethanolic benzene solution of this base with 2-propanolic hydrogen chloride yields a mono-hydrochloride which melts at about 242-244 C. with decomposition. The compound has the structural formula C H:i /CH3 i O-CO ((BHQQF'JF NH cn h I 2C 2 hot By substitution of 3-ethyl-2-piperazinone for the 3.3- dimcthyl-Z-piperazinone used in the preceding procedure, there is obtained Z-Chloro-lO-[7-(2-ethyl-3-oxopiperazinyl)propyllphenothiazine which is distilled in a shortpath distillation tube at 0.l mm. pressure and a jacket temperature of about 260 C.

Example 7 A mixture of parts of Z-piperazinone, 32 parts ot 90% formic acid and 23 parts of 36% formaldehyde is warmed. When the exothermic reaction has subsided the mixture is refluxed for 10 hours, cooled and then treated successively with 60 parts of solid sodium carbonate and 300 parts of chloroform. After stirring the mixture is filtered and the filtrate is vacuum distilled until an oily residue remains which crystallizes on cooling. The l-methyl-S-piperazinone thus obtained melts at about 79- 84 C. after recrystallization from ether.

A solution of 3.42 parts of this product in parts of toluene is treated with 1.29 parts of sodamide and the mixture is refluxed for 2 hours. Then a solution of 9.3 parts of 2-chloro-IO-(v-chloropropyl)phenothiazine in parts of dry toluene is added and refluxing is resumed for 7.5 hours. After cooling 20 parts of water are added and the organic layer is separated and extracted with dilute hydrochloric acid. This extract is rendered alkaline by addition of dilute potassium hydroxide and extracted with ether. The ether extract is dried over anhydrous calcium sulfate, filtered and evaporated and the residue is distilled in a short-path distillation tube at about 0.05 wherein Alk is a lower alkylene radical separating the mm. pressure and a jacket temperature of 220230 C. two nitrogen atoms attached thereto by at least two carbon to yield as an oily product 2-chloro-10-['y-(2'-oxo-4'- atoms. methylpiperazinyl)propyl1phenothiazine which has the 3. A compound of the structural formula structural formula 6 1 101 N on \N o l (lHQg-N N OH: (in )r N/ \NH CHQOH Use of an equivalent amount of l-benzyl-3-piperazinone for the 1-methyl-3-piperazinone used hereinabove yields 4. A compound of the structural formula 2-chloro-l0-[y-(2-oxo 4' benzylpiperazinyl]phenothiazine which is distilled in a short-path distillation tube at S\ about 0.2 mm. pressure and 270 C. jacket temperature.

Example 8 01 To a solution of 10.1 parts of 2-ch10r0-10-[7-(3'-0XO- piperazinyl)propyl]phenothiazine in 260 parts of toluene are added 1.5 parts of sodamide. The mixture is stirred (cam-N NH for 2 hours after which a solution of 3.6 parts of methyl iodide in 60 parts of toluene is added in small portions. The solution is heated to reflux for 5 hours and then 5 Acompound f h t u t ralfgnnula cooled and treated with Water. The organic layer is separated, washed with water and dried overanhydrous 8 sodium carbonate, filtered and evaporated. The residue 1 is submitted to short-path distillation at 0.05 mm. pres I sure and about 240 C. jacket temperature to yield 2-chloro-l0-[v-(3 oxo 4' methylpiperazinyDpropyl] phenothiazine. Its crude hydrochloride melts at about 1l5-118 C.

Substitution of 5 parts of ethyl iodide for the methyl A1kz N-(loweralkyl) iodide used in the preceding procedure yields 2-chlorolO-[7-(3' oxo-4-ethylpiperazinyl)propyllphenothiazine WhiCh'iS distilled at 0.2 mm. pressure and 260 C. jacket wherein Alk is a lower alkylene radical Separating the temperature. Similar substitution of an equivalent amount two nitrogen atoms attached thereto by at least two carbon of B-phenethyl iodide yields the 2-chloro-10-[y-(3'-oxo- 40 atonm Pheflethylpiperalinyl)Propynphenothiazine which is 6. A compound of the structural formula distilled in a short-path distillation apparatus at about 0.2. mm. pressure and 270-280 C.

What is claimed is: S 1. A compound of the structural formula s \N/ 01 X l CH: O N 1k--I\' NH I Alk-N N-R wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon (lower alkyl) O atoms 7. A compound of the structural formula wherein n is an integer between zero and two inclusive, X is a halogen atom of an atomic weight smaller than 40, S Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms, R is a member of the class consisting of hydrogen, lower 01 alkyl radicals and phenyl-(lower alkyl) radicals. N o

2. A compound of the structural formula 1 11 two nitrogen atoms attached thereto by at least two carbon atoms. 7 No references cited.

s lk--N N-(lower alkyl) N 01 wherein Alk is a lower alkylene radical separating the l 0 

1. A COMPOUND OF THE STRUCTURAL FORMULA 